Metal complexes as specific enzymatic inhibitors for the treatment of Leishmaniasis: cysteine-proteases and trypanothione reductase

• Grant number: 22/06410-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2022
• Status: Discontinued
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Camilla Abbehausen
• Grantee: Josielle Vieira Fontes
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 24/04343-4 - Organometallic Compounds for Anticancer Applications: PROTACs targeting, BE.EP.DR

Abstract

Leishmaniasis is a neglected tropical disease caused by the protozoan of the genus Leishmania and is considered endemic in Brazil. Currently available treatments are highly toxic (not very selective) and expensive, which has led the scientific community to investigate potential new drugs that specifically target the disease.In this context, two enzymes constitute attractive targets, especially for metallodrugs, the Cysteine-Proteases (CP) and Trypanothione Reductases (TR). They are responsible for parasite nutrition, reproduction, and defense, and both bear a cysteine in their active sites, constituting enhanced points for soft acids binding, such as Cu(I) and Au(I). Thus, the proposal of this project consists not only in the synthesis of complexes of Au(I) and Cu(I) with N-heterocyclic carbenes but in a systematic structural modification using R groups with known inhibitory characteristics, including small groups and the bioconjugation of inhibitory peptides. The ability of these complexes to inhibit CP or TR will be assessed. In vitro activity on Leishmania promastigotes and amastigotes will also be evaluated, in addition to a cellular internalization to investigate the mechanisms of action. (AU)